A phase I study of an agonist CD40 monoclonal antibody (CP-870,893) in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma.
A phase I study of an agonist CD40 monoclonal antibody (CP-870,893) in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma.
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DOI：
10.1158/1078-0432.ccr-13-1320
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发表时间：
2013-11-15
期刊：
影响因子：
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通讯作者：
O'Dwyer PJ
中科院分区：
文献类型：
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作者：
Beatty GL;Torigian DA;Chiorean EG;Saboury B;Brothers A;Alavi A;Troxel AB;Sun W;Teitelbaum UR;Vonderheide RH;O'Dwyer PJ
这项I期研究调查了CD40激动剂抗体CP-870,893与吉西他滨联合应用于晚期胰腺导管腺癌(PDA)患者的最大耐受量(MTD)、安全性、药效学、免疫学相关性和抗肿瘤活性。22例化疗初治的晚期PDA患者给予吉西他滨1000 mg/m2，每周1次，共3周，同时给予CP-870、893 0.1 mg/kg或0.2 mg/kg静脉滴注，每28天为1个周期。CP-870,893耐受性良好；在0.2 mg/kg剂量水平上出现1次剂量限制性毒性(4级脑血管事故)，估计为MTD。最常见的不良事件是细胞因子释放综合征(1~2级)。CP-870,893的输注引发免疫激活，表现为炎症细胞因子增加，共刺激分子B细胞表达增加，B细胞一过性耗竭。4例患者部分缓解(PR)。[18F]-氟代脱氧葡萄糖正电子发射断层扫描/计算机断层扫描(FDG-PET/CT)显示，8例患者中有6例原发胰腺病变FDG摄取减少25%；然而，在转移性病变中观察到的反应是不同的，一些病变完全丧失FDG摄取，而同一患者的其他病变无反应。总存活率的提高与肝脏病变中FDG摄取量的减少相关(R=−0.929；p=0.007)。CP-870,893与吉西他滨联合使用耐受性良好，并与PDA患者的抗肿瘤活性有关。在PET/CT成像上检测到的FDG摄取的变化提供了对治疗益处的洞察。第二阶段的研究是有必要的。
This phase I study investigated the maximum-tolerated dose (MTD), safety, pharmacodynamics, immunological correlatives, and anti-tumor activity of CP-870,893, an agonist CD40 antibody, when administered in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma (PDA). Twenty-two patients with chemotherapy-naïve advanced PDA were treated with 1000 mg/m2 gemcitabine once weekly for 3 weeks with infusion of CP-870,893 at 0.1 mg/kg or 0.2 mg/kg on day 3 of each 28 day cycle. CP-870,893 was well-tolerated; one dose-limiting toxicity (grade 4 cerebrovascular accident) occurred at the 0.2 mg/kg dose level, which was estimated as MTD. The most common adverse event was cytokine release syndrome (grade 1 to 2). CP-870,893 infusion triggered immune activation marked by an increase in inflammatory cytokines, an increase in B cell expression of co-stimulatory molecules, and a transient depletion of B cells. Four patients achieved a partial response (PR). [18F]-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) demonstrated >25% decrease in FDG uptake within primary pancreatic lesions in 6 of 8 patients; however, responses observed in metastatic lesions were heterogeneous with some lesions responding with complete loss of FDG uptake while other lesions in the same patient failed to respond. Improved overall survival correlated with a decrease in FDG uptake in hepatic lesions (R = −0.929; p = 0.007). CP-870,893 in combination with gemcitabine was well-tolerated and associated with anti-tumor activity in patients with PDA. Changes in FDG uptake detected on PET/CT imaging provide insight into therapeutic benefit. Phase II studies are warranted.